Research has found that all of the lymphomas associated with AIDS and most lymphomas in other immunocompromised persons are connected with latent EBV infection. EBV has been found in biopsy tissue of patients with Hodgkin's disease, breast cancer, and some smooth muscle tumors. EBV also was formerly suspected as the cause of chronic fatigue syndrome (originally named chronic EBV syndrome) (Encyclopedia: Epstein-Barr virus, Sixth Edition, Copyright © 2006 Columbia University Press).
EBV infection seldom lasts for more than 4 months. When such an illness lasts more than 6 months, it is frequently called chronic EBV infection. However, valid laboratory evidence for continued active EBV infection is seldom found in these patients. The illness should be investigated further to determine if it meets the criteria for chronic fatigue syndrome...(National Center for Infectious Diseases Epstein-Barr Virus and Infectious Mononucleosis, Updated:08/25/200).
Chronic fatigue symdrome results from low ATP output from mitochondria that have suffered oxidative damage and mDNA depletion associated with free radical stress and quite possibly in people with low Co-enzyme Q10 production. This enzyme is important in the process of utilization of ATP molecules for cellular energy and excess free radicals can disrupt the 17-step process for its production in cells (see: Is Malnutrition and Oxidative Stress the Cause of gp41, gp120 and gp160 in Robert Gallo's HIV Isolate? and HIV-Aids: A Tragic Error - Health Supreme, and Are AIDS, CFS Caused By Oxidative Damage?).
EBV is kept in check by a healthy immune system but its dormancy within the immune system is rather interesting and provides a direct link between the reactivated EBV, immunesuppression and the progression of AIDS as the Epstein-Barr virus appears capable of infecting only two major cell types: the outer (epithelial) cells of the salivary gland, and white blood cells known as B lymphocytes (B-cells) and infection of B-cells by the virus results in its proliferation as the antibodies cannot bind with it in the B-cells and the T-cells cannot attack the infected B-cells (see;Nova Science in the News, Australian Academy of Science, Nov 1997). If this explaination holds true, it offers a insight into Reactivated EBV-AIDS or REBV-AIDS and further rules out the Gallo HIV virus that is supposedly a virulent pathogen that specifically targets the immune system that was stated to be "the probable cause of AIDS".
"These are complex enveloped DNA viruses, which multiply in the nucleus of the host cell. EBV infects resting human B-lymphocytes and epithelial cells, multiplies in the latter and establishes latent infection in memory B-lymphocytes. Thus, infected individuals may produce virions, carry virus-specific CTLs, produce EBV-specific antibody, and yet harbor latently infected memory B-cells. These maintain the latent EBV genome as an episome that expresses only part of its genetic information, including EBV nuclear antigens EBNA-1 (a latent DNA replication factor), EBNA-2 (a transcriptional activator) and EBNA-3A and -3C (involved in the establishment of latency), together with integral membrane proteins LMP-1 and LMP-2 which play major roles in maintenance of latency and escape from the immune response of the host. Latently infected cells do not produce the B7 coactivator receptor and, therefore, are not killed by CTLs. When peripheral blood from an infected individual is cultured, latently infected B-cells begin to replicate and yield immortalized progeny lymphoblasts that can be indefinitely propagated in the laboratory" (WHO/IVB/05.XX; Viral Cancers).
The Epstein-Barr virus (EBV) resides as a persistent infection in human leukocyte antigen (HLA) class II+ B lymphocytes and is associated with a number of malignancies. The EBV lytic-phase protein gp42 serves at least two functions: gp42 acts as the coreceptor for viral entry into B cells and hampers T-cell recognition via HLA class II molecules through steric hindrance of T-cell receptor-class II-peptide interactions (Maaike E. Ressing et al, Epstein-Barr Virus gp42 Is Posttranslationally Modified To Produce Soluble gp42 That Mediates HLA Class II Immune Evasion, Journal of Virology, January 2005, p. 841-852, Vol. 79, No. 2).
Hutt-Fletcher and her colleague Corina M. Borza recently published their study and some unexpected observations in the June Nature Medicine. In laboratory dishes, epithelial cells are a bit more easily infected by Epstein-Barr virus that was first grown inside B cells than by virus previously grown in epithelial cells. Even more dramatic, Hutt-Fletcher and Borza found that Epstein-Barr virus grown inside epithelial cells is 30 to 100 times more efficient at infecting B-cells than the virus grown in B cells themselves. This suggests an interesting difference in form between the two.
Molecules on the virus' surface that the virus uses to gain access to cells might explain this phenomenon. To infect epithelial cells, Epstein-Barr virus seems to depend upon a complex of two proteins, gH and gL. But to get into B cells, the virus needs a third protein, gp42, in the complex. The virus typically has both types of complexes on its surface, but their ratio influences the virus' preference for one cell or another. EBV virus grown in epithelial cells has more gp42-containing complexes than virus grown in B cells (Borza, C.M., and L.M. Hutt-Fletcher. 2002. Alternate replication in B cells and epithelial cells switches tropism of Epstein-Barr virus. Nature Medicine 8(June):594-599) and that enables them to gain entry into the B-cells of the immune system.
In general, no virus is produced during latent infection, but in a certain proportion of EBV infected cells, a reactivation of the viral lytic programme can be observed, with the release of mature infectious virions (Sugden B. Expression of virus-associated functions in cells transformed in vitro by Epstein-Barr virus: Epstein-Barr virus cell surface antigen and virus-release from transformed cells. In: Purtilo DT, ed. Immune deficiency and cancer. New York: Plenum Press; 1984:165 - 77).
Although EBV encodes as many as 11 glycoproteins, efficient entry of EBV into B cells requires only 5 glycoproteins: gp350/220, gH, gL, gB, and gp42 (Amanda L. Silva et al, Mutational Analyses of Epstein-Barr Virus Glycoprotein 42 Reveal Functional Domains Not Involved in Receptor Binding but Required for Membrane Fusion, JOURNAL OF VIROLOGY, June 2004, p. 5946â•„5956).
Ressing et al, demonstrated that the gp42 protein functions as an immune evasion molecule for HLA class II-restricted T-cell responses (Ressing, M. E., 2003. Interference with T cell receptor-HLA-DR interactions by Epstein-Barr virus gp42 results in reduced T-helper cell recognition. Proc. Natl. Acad. Sci. USA 100:11583-11588) and that spefically allows its entry into the B-cells of the immune system and from there it can proliferate wildly if reactivated producing toxins that precipitate disease conditions.
The toxins of the reactivated and proliferating EBV in all likelihood cause damage to tissues in any system of the body. When its toxins concentrate in the endothelium and cause endothelial dysfunction, the excess NO could result in multiple sclerosis and if the NO reacts with ROS forming the reactive peroxynitrite free radical, other disease states could develop. An interesting hypothesis is that its toxins may damage the oxygen molecule to produce the superoxide radical thereby producing the twin effects of;
1. Firstly, a feeling of tiredness and general mailaise, and
2. Damaging cell membranes and altering the pH value in the cytoplasm by increasing the acidity
that in turn inactivates the enzymes involved in the Kreb's causing a drop in ATP output and finally leading to the rerouting of glucose into the glucose-alcohol (anaerobic) pathway that transform the cell into a cancer cell.
This biochemistry fits into the view of EBV associated diseases, including tiredness, general malaise, chronic fatigue and AIDS. Equally AIDS can develop through oxidative stress alone, especially in malnourished people and when both factors are taken together, a mathematical model would more accurately describe the prevalence of AIDS from African countries to the developed nations. In African countries such as Uganda, in the lymphoma belt, the association of BL with EBV is very strong (97%), whereas it is weaker elsewhere (85% in Algeria; only 10 - 15% in France and the USA).
So, two critically important questions must be answered. First, how does EBV selectively infects memory B-cells in humans and secondly what triggers the reactivation of EBV that lies dormant in the B-cells of the human immune system? In vitro culture of rat natural killer (NK) cells in high concentrations of recombinant interleukin 2 (rIL-2) leads to the expression of a surface glycoprotein with a molecular mass of approximately 42 kD. This glycoprotein, gp42, is not induced on other lymphocytes and thus provides a lineage-specific marker for rIL-2- activated NK cells (WE Seaman, Molecular cloning of gp42, a cell-surface molecule that is selectively induced on rat natural killer cells by interleukin 2: glycolipid membrane anchoring, and capacity for transmembrane signaling, Journal of Experimental Medicine, Vol 173, 251-260, Copyright © 1991 by Rockefeller University Press). Thus, gp42, the only NK-specific activation antigen, is a GPI-anchored surface molecule with the capacity to re-enter the NK cells and if it binds with another agent or molecule or viral parts, the entire complex can enter the NK cells and the gp42 glycoprotein serves as an immune-evasion mechanism to the whole gp42-viral complex in rats.
Recent reports suggest that the EBV infection is closely associated with mature natural killer (NK) cell malignancies in humans, too but there has been no direct evidence that EBV infects human NK cells in vitro (ref: Yasushi Isobe, Epstein-Barr Virus Infection of Human Natural Killer Cell Lines and Peripheral Blood Natural Killer Cells, Immunology, Cancer Research 64, 2167-2174, March 15, 2004).
Whereas, viral glycoproteins, gp42 and gp85, are known to play an important role in EBV internalization into HLA class II-positive cells (Molesworth SJ et al, Epstein-Barr virus gH is essential for penetration of B cells but also plays a role in attachment of virus to epithelial cells. J Virol, 74: 6324-32, 2000: Borza CM and Hutt-Fletcher LM. Alternate replication in B cells switches tropism of Epstein-Barr virus. Nat Med, 8: 594-9, 2002), oxidative stress caused by superoxide free radicals may be the facilitating factor that allows entry of EBV into human NK cells.
The issue in human EBV infection, however, is in large proportion related to B-cell infection. The key to explaining EBV infection in humans lies in oxidative stress on the cell membrane of B-cells and the consequent decline of oxygen in the cell. The process of phagocytosis requires the polymerization of actin in a directional fashion to surround and internalize the target. Actin polymerization is dependent on adequate supplies of ATP. Exposure to hyperoxia can impair the activity of cellular enzymes important in oxidative metabolism, which could lead to increased anaerobic glycolysis, depletion of glucose in the cell growth medium, and subsequent depletion of ATP. However, ATP levels in RAW 264.7 cells cultured in hyperoxia were not reduced. Glucose content in the cell growth medium was higher in the hyperoxic cultures, likely as a result of inhibition of cell proliferation by hyperoxia. Examination of the actin cytoskeleton of RAW 264.7 cells cultured in hyperoxia, by immunofluorescence microscopy, revealed marked changes, including an increase in the degree of actin polymerization, loss of cortical actin, and the formation of prominent stress fibers and actin aggregates (see Philip J et al, Hyperoxia Impairs Antibacterial Function of Macrophages Through Effects on Actin, American Journal of Respiratory Cell and Molecular Biology. Vol. 28, pp. 443-450, 2003).